The hypothesis that inflammatory cytokines play a role in the pathophysiology of psychiatric disorders stems from the observation that sickness behavior is characterized by signs and symptoms that are common to major depression. Sickness behavior is a nonspecific reaction to inflammation that is mediated by proinflammatory cytokines (eg, interleukin (IL)-1, IL-6, tumor necrosis factor α [TNF-α], and interferon-γ [IFN-γ]) and is characterized by decreased appetite, amotivation, cognitive impairment, and neurovegetative symptoms.
Inflammatory cytokines in psychiatry
During the past 2 decades, numerous studies have documented abnormal inflammatory cytokine concentrations in patients with MDD, bipolar disorder, or schizophrenia.6-9 Most replicated and common to all 3 conditions are elevated concentrations of circulating TNF-α, IL-6, and IL-1β. Preliminary evidence also documents abnormalities in concentrations of proinflammatory cytokines in the cerebrospinal fluid of patients with MDD, bipolar disorder, or schizophrenia.10-12 It has been hypothesized that inflammation in mood disorders may arise from an imbalance between proinflammatory and anti-inflammatory cytokines. This is supported by evidence of increased proinflammatory to anti-inflammatory cytokine ratios in these populations.13-15
There is a pressing need for studies of inflammatory markers in children and adolescents at risk for or in the early stages of a psychiatric disorder. At this point, it is not known if inflammatory cytokine abnormalities are a cause or consequence of the illness. Preliminary evidence suggests that manic but not depressive symptom severity in adolescents with bipolar disorder is significantly associated with high-sensitivity C-reactive protein (CRP) levels, an acute phase reactant that is elevated in response to inflammation, but not with IL-6 levels.16 A preliminary proinflammatory gene expression signature has been reported in offspring of individuals with bipolar disorder, and elevated messenger RNA (mRNA) levels as well as protein expression levels of IL-1β, IL-6, and TNF-α have been reported in the prefrontal cortex of adolescent suicide victims.17,18 Longitudinal studies in children at genetic risk for major psychiatric disorders may aid identification of biomarkers that allow for earlier detection of candidates for prophylactic treatment.
Although the triggers of inflammation in psychiatric disorders are unknown, they are likely multifactorial in origin and encompass environmental and genetic factors (Figure). For example, maternal infections as well as maternal stress have been reported to pose a risk for the onset of schizophrenia later in life.19,20 Early childhood stress has also been shown to trigger an inflammatory response and may render individuals more vulnerable to psychiatric disorders.
Among female adolescents at high risk for depression, transition to depression was associated with increases in CRP and IL-6 levels; the magnitude of these changes was greater among females with multiple types of childhood adversity.21 Lower socioeconomic status in early childhood (1 to 2 years of age) has also been associated with elevated circulating IL-6 levels in adulthood.22 Environmental factors during the prenatal period or early childhood may activate the inflammatory response, which in combination with a genetic susceptibility or epigenetic modification, may increase the risk of psychiatric disorders.
Inflammation is highly interconnected with oxidative stress and results in a widespread influence on protein expression and cell survival. Oxidative stress exerts effects on DNA methylation patterns and produces unique epigenetic profiles that may increase vulnerability to psychiatric disorders. For example, decreased IL-6 CpG methylation is associated with elevated serum IL-6 and CRP levels in individuals with lifetime depression.23 Moreover, inflammation and oxidative stress are associated with increased apoptosis and decreased neural and glial plasticity.24 Abnormalities in these processes have also been reported in persons with MDD, bipolar disorder, and schizophrenia.25-27